Androgen receptor requires JunD as a coactivator to switch on an oxidative stress generation pathway in prostate cancer cells.
Androgen receptor requires JunD as a coactivator to switch on an oxidative stress generation pathway in prostate cancer cells.
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DOI：
10.1158/0008-5472.can-09-3596
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发表时间：
2010-06-01
期刊：
影响因子：
11.2
通讯作者：
Wilding G
中科院分区：
文献类型：
--
作者：
Mehraein-Ghomi F;Basu HS;Church DR;Hoffmann FM;Wilding G
前列腺中相对高的氧化应激水平被认为是前列腺癌发生和前列腺癌（CaP）进展的主要因素。我们专注于阐明CaP细胞中氧化应激产生的代谢途径。以前，我们表明，转录因子JunD是雄激素依赖性人前列腺癌细胞中雄激素诱导的活性氧（ROS）产生所必需的。我们最近还证明，雄激素诱导的第一个和调节酶亚精胺/精胺N1-乙酰转移酶（SSAT）的多胺分解代谢途径，产生大量的代谢活性氧。在这里，我们提出了免疫共沉淀和高斯荧光素酶重建试验数据，显示JunD形成一个复合物与雄激素激活的AR原位。我们的染色质免疫沉淀试验数据表明，JunD直接结合到一个特定的SSAT启动子序列，只有在雄激素处理的LNCaP细胞。使用含有荧光素酶报告基因连接到SSAT启动子和JunD沉默的LNCaP细胞系的载体，我们表明，JunD是雄激素诱导的SSAT基因表达所必需的。JunD-AR复合物诱导SSAT表达导致多胺氧化的阐明建立了CaP细胞中雄激素诱导的ROS产生的机制基础，并为CaP化学预防/化疗药物开发开辟了新的前列腺特异性靶点。
Relatively high oxidative stress levels in the prostate are postulated to be a major factor for prostate carcinogenesis and prostate cancer (CaP) progression. We focused on elucidating metabolic pathways of oxidative stress generation in CaP cells. Previously, we showed that transcription factor JunD is essential for androgen-induced reactive oxygen species (ROS) production in androgen-dependent human prostate cancer cells. We also recently demonstrated that androgen induces the first and regulatory enzyme spermidine/spermine N1-acetyl transferase (SSAT) in a polyamine catabolic pathway that produces copious amounts of metabolic ROS. Here, we present co-immunoprecipitation and Gaussia luciferase reconstitution assay data that show JunD forms a complex with androgen-activated AR in situ. Our chromatin immunoprecipitation assay data demonstrate that JunD binds directly to a specific SSAT promoter sequence only in androgen-treated LNCaP cells. Using a vector containing a luciferase reporter gene connected to the SSAT promoter and a JunD-silenced LNCaP cell line, we show that JunD is essential for androgen-induced SSAT gene expression. The elucidation of JunD-AR complex inducing SSAT expression leading to polyamine oxidation establishes the mechanistic basis of androgen-induced ROS production in CaP cells and opens up a new prostate specific target for CaP chemopreventive/chemotherapeutic drug development.